The group of Δ2-isoxazoline derivatives 5a–c and 6a–c, structurally related to epibatidine, and the simplified analogues 7a–c were synthesized by means of a 1,3-dipolar cycloaddition-based strategy and tested at α4β2 and α7 neuronal acetylcholine receptor (nAChR) subtypes. Competition binding experiments at α4β2 nAChR subtypes showed an overall significant reduction in affinity for the compounds under study in comparison to the reference radioligand [3H]-epibatidine. These outcomes have been rationalized by taking into account the ligand-based pharmacophore models reported in the literature and the recently proposed molecular model of the α4β2 receptor subtype. Conversely, compounds 5b, 5c, and 6b exhibited a noticeable affinity for the α7 receptors and, in the case of 5c, also some subtype selectivity